Two SNPs SN-38 mouse rs1133973 and see more rs3205088 were monomorphic in our population. Table 1 Basic characteristics of two studied cohorts   Hong Kong Southern Chinese extreme cohorta Hong Kong Osteoporosis Study prospective cohortb High BMD group Low BMD group P value BMD group Vertebral fracture No fracture group With fracture group P value Subjects number 663 909   2,509 1,469 277   Age (years) 47.7 (15.46) 50.5 (16.02) <0.05 63.6 (8.81) 62.4 (8.31) 68.0 (9.10) <0.01 Height (m) 1.61 (0.08) 1.55 (0.08) <0.01 1.56 (0.08) 1.57

(0.08) 1.54 (0.08) <0.01 Weight (kg) 63.59 (10.91) 50.73 (8.66) <0.01 57.65 (10.12) 58.04 (10.02) 56.80 (10.77) 0.06 BMD (g/cm2)  Lumbar spine 1.09 (0.13) 0.74 (0.13) <0.01 0.85 (0.18) 0.87 (0.18) 0.80 (0.18) <0.01  Femoral neck 0.86 (0.12) 0.58 (0.09) <0.01 0.65 (0.12) 0.67 (0.12) 0.60 (0.13) <0.01 BMD z-score  Lumbar spine 1.16 (0.84) −1.43 (0.68) <0.01 −0.24 (1.13) −0.17 (1.34) −0.40 (1.25) <0.05  Femoral neck 1.10 (0.82) −1.25 (0.66) <0.01 −0.20 (0.98) −0.11 (0.99) −0.36 (1.03) <0.01 Data are expressed as mean (SD). The t test was conducted for phenotype comparison between check details high and low BMD groups for extreme cohort and between groups with and without vertebral fracture for prospective cohort aThe basic characteristics of the lumbar spine and femoral neck sub-groups of the extreme cohort are detailed in Table S1 (ESM 1) bA total of 2,509 subjects with BMD data were included in the prospective cohort, and 1,746 of them had the data of vertebral fracture Table 2 Association results of eight polymorphic SNPs with BMD variation in the tSNP-based association study (HKSC extreme cohort, n = 1,572) SNP

Genomic position Genic position Alleles major/minor MAF HWE (P) Either LS or FN LS FN P value OR 95%CI P value OR 95%CI P value OR 95%CI rs9547952 37036688 Exon 22 C/T 0.075 0.747 >0.1 1.08 0.74–1.49 EGFR inhibitor >0.1 1.10 0.68–1.63 >0.1 1.02 0.63–1.66 rs9603226 37041585 Intron 20 G/A 0.339 0.413 >0.1 0.84 0.69–1.03 >0.1 0.92 0.71–1.16 0.056 0.76 0.56–1.00 rs7322993 37051129 Intron 14 C/T 0.195 0.666 0.001* 1.46 1.16–1.82 0.006* 1.47 1.12–1.93 0.029 1.45 1.03–1.99 rs7323378 37051350 Intron 13 T/C 0.113 1.000 >0.1 1.02 0.77–1.35 >0.1 1.05 0.74–1.49 >0.1 0.88 0.59–1.33 rs9547965 37051887 Intron 12 G/A 0.028 0.145 >0.1 0.76 0.47–1.28 >0.1 0.91 0.50–1.63 0.050 0.47 0.22–1.01 rs17056105 37055419 Intron 9 A/T 0.082 0.372 >0.1 1.21 0.87–1.65 >0.1 1.14 0.77–1.67 >0.1 1.28 0.79–2.05 rs12871092 37057632 Intron 7 A/G 0.353 0.858 >0.1 0.90 0.76–1.12 >0.1 0.83 0.67–1.08 >0.